DE1768659B2 - METHOD FOR MANUFACTURING BETA SINENSAL - Google Patents

Description

, ACU ₂ X

in which X denotes bromine or) od, with an N-substituted ethanalimine whose substituent is one straight-chain or branched aliphatic or aücyclischer radical with 2 to 8 carbon atoms, condensed in the presence of a metallizing agent and the condensation product in one at least partially hydrolyzed aqueous acidic medium to 4-methyl-8-vinylnonadien- (4,8) -al.

The invention relates to a process for the production of "-Sinensal" which has the following formula Has:

^ -Sinensal is a sesquiterpene aldehyde contained in a Orangenart, Citrus sinensis (see J. Org. Chem. 30,1690

[1965]) and which, thanks to its taste properties, is used as a flavoring substance for the Flavoring food, beverages and pharmaceuticals and for the manufacture of artificial ones Flavors and artificial essential oils can be used

} o is.

Next to the /? - Sinensa! In the same type of orange there is also the Λ-sinensal, which has the same formula wL · the / 3-compound with the exception that instead of the double bond in the 10-exo position there is a double bond in the 9,10-position. In earlier publications there is a nomenclature that differs from the now usual, in which λ and β are interchanged.

So far it was not successful., Ss-Sinensa! on synthetically produced. It has now been found that one can easily obtain J3-Sinensal from Can produce raw materials synthetically.

The process for the production of | 9-Sinensal der The above formula is now characterized in that

45 man

a) Myrcene on the non-conjugated double bond using a peracid in a buffered one The medium is epoxidized in such a way that the solution to be epoxidized is cooled and the epoxidation

5c medium under cooling with such

Speed admits that the resulting reaction temperature remains roughly constant:

b) the myrcene epoxide obtained under basic bonds in the corresponding secondary Alcohol over him:

c) the latter with an unsubstituted vinyl ether in the presence of a mixture of a heavy metal salt and an alkali metal salt acting as a stabilizer condensed:

<io d) the aldehyde obtained. 4-methyl-8-vinylnonadiene- (4.8) -al with an N-substituted propionalimine, the substituent of which is a straight-chain or branched aliphatic or alicyclic radical having 2 to 8 carbon atoms. in present

(15 of a metallizing agent condensing ".:

e) the condensation product then in an at least partially aqueous acidic medium / u / J-Sinensa! hydrolyzed.

According to the invention, steps a) to c) are carried out according to the following scheme

Peracid

Myrcene

Epoxy opening of the
Epoxy rings

sec-myrcenol
/ ^ OR

CHO

The peracid used for the epoxidation [stage a)] can, for example, be peracetic acid. Perbenzoic acid. Monochloroperbenzoic acid or perphthalic acid $ em. The solvents used are chlorinated hydrocarbons, for example chloroform, methylene chloride. Chlorethylene or dichloroethane can be used. Advantageous is the use of peracetic acid in methylene chloride. Suitable as buffer substances for example organic alkali salts such as sodium or potassium formate, acetate, propionate, butyrate, oxalate. citrate or tartrate. Sodium acetate is advantageously used.

The selective epoxidation of the non-conjugated double bond of myrcene while avoiding attack on the other double bonds is a critical operation and must be carried out under carefully controlled conditions if good yields of the desired peroxide are to be achieved. It was z. B. found that the control of the reaction temperature by the usual methods is inadequate. The cooling capacity of the temperature control device (cooling apparatus) should be such that after the addition of the epoxidizing agent has started at a certain rate, the temperature rises rapidly to a certain level and remains practically constant until the addition of the epoxidizing agent has ended. To obtain optimum yields example, it is convenient to cool the reaction vessel to about O ⁰ C and the epoxidizing agent added dropwise at such a rate to admit that the temperature first rises to 20-25 ⁰ C and then remains practically constant at this level without the cooling device must be put out of operation.

The secondary alcohol corresponding to the myrcene epoxide (hereinafter referred to as sec-myrcenol) is obtained by opening the epoxy ring. The ring opening takes place under basic conditions.

To convert the myrcene epoxide into sec-myrcenol, an organometallic base, e.g. B. a Use metal dialkylamide in a non-reactive solvent such as lithium, sodium or potassium diisopropylamide, diisobutylamide or dicyclohexylamide in ether, benzene, dioxane or Cyclohexane. A solution of lithium diisopropylamide in cyclohexane is advantageously used.

The condensation of the sec-Myrcenol with an unsubstituted vinyl ether is in the presence of a Condensation agent carried out. A mixture of a visco metal salt is used as the condensation agent with an alkali metal salt acting as a stabilizer.

Heavy metals are those that have the Have the property of forming metal-organic complexes / u, e.g. B. Mercury. Silver. Lead. Copper. Iron. Palladium. Cobalt and magnesium. The salts mentioned should preferably be in the organic reaction medium be at least partially soluble. The acids. \ un ίο which the named salts are derived from expediently organic acids, for example Formic, acetic, propionic or citric acid. As a precaution a mixture of mercury acetate and sodium acetate is used as the condensing agent. The unsubstituted vinyl ethers used for the condensation are methyl, ethyl, propyl, isopropyl or butyl vinyl ethers and other alkyl vinyl ethers can be used. the end It is advantageous because of the easy accessibility of the wedge. Use ethyl vinyl ether or butyl vinyl ether. The condensation can take place over a wide temperature range and using an excess of vinyl ether as a solvent in an inert atmosphere be performed. Advantageously, condensation is used at the boiling point of the door ate Vinyl ethers worked.

The reaction product of an alkali metal with an alkyl halide and a secondary amine can, for example, be used as the metallization medium for stage d). Sodium, potassium or lithium or their alloys, for example, can be used as alkali metals. Suitable alkyl halides are those having 1 to 6 carbon atoms, for example
Methyl iodide, ethyl iodide, ethyl bromide,
n-propyl bromide, n-propyl iodide, isopropyl bromide, isopropyl iodide, butyl chloride, butyl bromide,

Amyl bromide, isobutyl iodide, hexyl chloride,
Hexyl bromide and hexyl iodide.
As secondary amines, for example
Diethylamine, diisopropylamine, piperidine,
Dicyclohexylamine, piperazine, dibutylamine,
Diisobutylamine and ethyl-tert-butylamine
be used. The reaction product of lithium metal with methyl iodide and diisopropylamine is advantageously used as the metallizing agent.
(\ s The N-substituted propionalimine used in the process according to the invention can, for example
N-ethyl-, N-cyclohexyl-, N-methylcyclohexyl-,
N-tert-butyl-, N-propyl-, N-isopropyl-,

N-isobutyl-, N-sele-butyl-, N-amyl- or N-neopentyl propionalimine

be. N-Cyciohexyl-propionalimine and N-tert-butyl-propionalimine are advantageously used. The imines mentioned can be prepared by known methods (see Bull. Soc. Chim. Franc «. 14,708 [1947]).

The condensation according to step d) may be at temperatures from -80 0 of about ⁰ C in an inert atmosphere, for example at about -6O ⁰ C under nitrogen ι ο be performed.

Aqueous acidic media such as are suitable for the hydrolysis of the condensation product in step e) Mixtures of mineral acids or organic acids with at least partially aqueous solvents. as Acids can, for example, be phosphoric acid. Sulfuric acid, perchloric acid, hydrochloric acid. Oxalic acid, acetic acid, Trifluoroacetic acid, tartaric acid, malic acid and citric acid can be used. As a solvent are water and mixtures of water with a water-miscible solvent, for example methanol. Ethanol, acetone, dioxane, tetrahydrofuran and dimethoxyethane. usable. Advantageously used using aqueous oxalic acid as the hydrolysis medium.

According to the invention you can according to Siuleii .1} bis c) also produce the aldehyde obtained by a Myreenyl halide of the formula:

CH ₂ X

in which X represents bromine or iodine, with a N-substituted ethanal-imine, whose substituent is a straight or branched aliphatic or alicyclic radical having 2 to 8 carbon atoms is in The presence of a metallizing agent condenses and the condensation product is then hydrolyzed in an at least partially aqueous acidic medium.

The reaction product an alkali metal with an alkali halide and a secondary amine. As alkali metals Sodium, potassium and lithium as well as alloys of these metals are suitable. As alkyl halides can be those with 1 to 6 carbon atoms, for example so

Methyl iodide, ethyl iodide or bromide.
N-propyl bromide or iodide, isopropyl bromide or iodide, butyl chloride, bromide or iodide,
Amyl bromide, isobuiyl iodide, hexyl chloride, bromide or iodide,

be used. Examples of suitable secondary amines are

Diethylamine, diisopropylamine, piperidine,
Dicyclohexylamine, piperazine, dibutylamine. <«,

Diisobutylamine, and ethyl-tert-butylamine.
The reaction product of lithium metal, methyl iodide and diisopropylamine is advantageously used,

The N-substituted ethanalimine can be, for example, fts way

N-ethyl-, N-cyclohexyl-, N-methylcyclohexyl-,
N-tcrt.-butyl-, N-propyl-, N-is.opropyl-,

N-isobutyl, N-seL-butyl, N-amyl or

N-neopentylethanolimine

use. It is advantageous to use N-cyclohexyl- or N-tett-butyl-ethynylimine. The imines listed above can be prepared by known methods (see Bull. Soc. Chim. France 14, 708 [1947]).

The myrcenyl halide can be obtained from the corresponding primary myrcenol by the methods customary for the halogenation of alcohols. The latter alcohol can be obtained by oxidation of marcene (Bull. Soc. Chim. Frances, 931 [1938]). Phosphorus bromide or triiodide are suitable as halogenating agents.

The condensation of the Myrcenylhalogenids with the Äthanalimin ⁰ C. can advantageously at about -20 ⁰ C, are carried out under stick material at temperatures from -60 C to O.

As at least tcifwe se aqueous acidic medium Uj ₁ -.! Ic hydrolysis of the condensation product one can use mixtures ion mineral or organic Siu.rcn at least partially aqueous LösungMiiateil ·. Examples of suitable acids are phosphoric acid. Sulfuric acid. Perchloric acid. Hydrochloric acid. Oxalic acid, acetic acid, trifluoroacetic acid. Tartaric acid. Malonic acid and citric acid. The use of aqueous oxalic acid is particularly advantageous.

The following examples in which the temperatures are given in degrees Celsius / own, like the Invention can be carried out.

example 1

Manufacture of // - Sinensal

a) Epoxidation of myrcene

A solution of 204 g of freshly distilled technical myrcene. containing about 10% limonene and 1 50 g Sodium acetate in 750 ml of methylene chloride was stirred for 1 hour at room temperature and then cooled to OC within about 15 minutes. Afterward a solution of 3 g of sodium acetate in 315 g of 42% peracetic acid was added dropwise with such a solution Entered the speed that the temperature of the reaction mixture rose to 20-25 ° C. By maintaining a suitable rate of addition. but without removing the cooling device, the The temperature was kept constant until the addition of the peracetic acid was complete. Under these conditions the addition of the peracetic acid took about 1 hour. The reaction mixture continued for 4 hours stirred at room temperature, whereupon the solid by-product is filtered off and washed with methylene chloride was washed. The combined methylene chloride solutions were poured into ice water, whereupon the Mixture was shaken vigorously and the organic layer was separated. The latter was made with servings of Washed 125 ml of the following solvents: water (once), saturated sodium bicarbonate solution (twice), and water (once). After drying and concentrating the residue was distilled.

205 g of epoxymyrccn (90% yield) were obtained. Bp = 41-44 ° / 0.06 Torr.

Analysis for Ci <iHu, O:

Calculated: C 78.89, H 10.59%;
found: C 78.65, H 10.40%.

n: = 1.4632: d \ = 0.8865: Ul = - 3.95 '.

b) (1) Transfer of myreenepoxide
in sec-myrcenol

A cooled to -1O ⁰ C solution of 126.5 g (1,25MoI) of diisopropylamine in 500 ml of cyclohexane were within 20 minutes under vigorous stirring and nitrogen was added dropwise 465 g of a 15% strength solution of butyllithium in hexane was added. The reaction mixture was stirred for a further 10 minutes at 0 ° C., after which it was cooled to -5 ° C. and 76 g (0.5 mol) of epoxymyrcene were added dropwise over the course of 10 minutes. The temperature was then allowed to slowly decrease to 25 ° C. and kept constant at this level for 1½ hours. The reaction mixture was poured into ice water, whereupon the organic layer was separated off, washed first with 10% strength aqueous hydrochloric acid and then with water and finally dried. The individual wash waters were extracted with petroleum ether (250 ml), whereupon the extracts were combined, concentrated and distilled. 53 g (69.8%) of sec-myrcenol with a ^{boiling point of 47 c} / 0.04 Torr were obtained.

Analysis for CioHI ₆ O:
. Calculated: C 78.89. H 10.59%;
found: C 78.61. H 10.37%.

π Ϊ = 1.4890; ^d: = 0.8986; [λ] 2 = - 1.8.

b) (2) Transfer of myreenepoxide
in sec-myrcenol

A solution of 126.5 g of diisopropylamine in 300 ml of cyclohexane was added at - 10 ^r C under nitrogen was added dropwise in 465 g of an approximately 15% strength solution of butyllithium in hexane was added. Then, with vigorous stirring at -5 to 0 ^c C was added dropwise 76g Epoxymyrcen added. The reaction mixture was then stirred with 200 ml of ice water and neutralized with dilute hydrochloric acid. By working up in the manner described in paragraph b) (1), sec-myrcenol was obtained in approximately the same yield.

c) 4-methyl-8-vinyl-nonadiene- (4.8) -al

A mixture of 50 g sec-myrcenol. 300 g of n-Butylbinyl-ether, 1 g of mercuric acetate and 10 g sodium acetate was heated for 40 hours under nitrogen at reflux ^ s (120 ^c C). During this time, 1 g of additional mercuric acetate was added every 6 hours. The reaction flask was connected to a descending condenser and the excess n-butyl vinyl ether was distilled off at ordinary pressure. By distilling the residue under reduced pressure, 4-methyl-8-vinyl-nonadien- (4,8) -al, which still contained about 15% of unreacted alcohol, was obtained in a yield of 75%. This alcohol could be recovered when the aldehyde was converted into jJ-Sinensai.

d) j9-Sinensal

A 600 ml abs. Ether and 640 g of a 15% solution of butyllithium (1.5 mol) in hexane-containing solution was ^{cooled to -10 0} C. This solution was a solution of 128 g of diisopropylamine <1.265 mol) in 1 hour under nitrogen and with stirring 600 ml abs. Ether was added. The temperature was allowed to rise to 0 ^° C. and the reaction mixture was stirred for a further half an hour. After the reaction mixture had cooled to - NTC, a solution of 208 g of propylidene-cyclohexylimine (1.5 mol, bp = 56-58 ° / 15 Torr) in 600 ml of ether was added dropwise to it over the course of 1 hour. The reaction mixture was stirred for 1 hour at 0 ° C, then cooled to -65 ° C, and finally inside '/ 2 hour at a temperature of -66 ⁰ C to -62 ⁰ C a solution of 225 g of 4-methyl-8 -vinyl-nonadiene- (4.8) -al (1.265MoI) added to 600 ml of ether. The temperature of the reaction mixture was allowed to rise to 25 ° C. (within 1 hour), whereupon the reaction mixture was poured into a solution of 600 g of oxalic acid in 8 liters of water at 0 ° C. while stirring. The organic layer was separated and the aqueous phase was extracted twice with ether (2 liters). The extracts were washed first with 5% aqueous sodium bicarbonate solution and then with water. By drying and concentrating the extracts, crude O-Sinensal was obtained in 70% yield, boiling point = 100-111 ° / 0.04 Torr. For analytical purposes, a sample of silica was chromatographed using a 3% solution of ethyl acetate in hexane as the eluent. The purified product had a boiling point of 88-89 ° / 0.02 Torr. IR spectrum (CHCl ₃ ): 3090, 2710, 1800, 16 * 0. 1640, 1590, 995, 905 to ¹ . UV spectrum (ethanol): 2260 Λ (ε = 34000). Nuclear Magnetic Resonance Spectrum (CCU): 9.33 ppm (1 H, s). 6.37 ppm (1 H, t. 1 = 6cps), 6.30 ppm (1 H. d of d, | = 17 and 10cps). 4.8-5.4 ppm (5 H. m). 1.9-2.6 ppm (8H, m). 1.69 ppm (3 H. s broad). 1.61 ppm (3 H. s broad).

Analysis for Q5H22O:
Calculated: C 82.51. H 10.16%:
found: C 82.58. H 10.39%.

The / 3-Sincnsal dinurophenyihydrazone melted at 86-88 = C.

Example 2

Manufacture of /} - Sincnsa!

a) Production of myrcenyl bromide

A solution was prepared from 52.4 g (345 millimoles) of myrcenol (prepared from myrcene according to Bull. Soc. Chim, 5, 931 [1938]), 8.5 g (105 millimoles) of anhydrous pyridine and 200 ml of anhydrous hexane, which at -10 ° C A solution of 40.5 g (105 millimoles) of phosphorus tribromide was added dropwise with stirring. The reaction mixture was ^{stirred for a further 30 minutes at O 1} X and then 200 g of ice were added in portions. After further stirring for 30 minutes at room temperature, the organic layer was separated and Washed first with water, then with 5% aqueous sodium bicarbonate solution and finally with water The extract was dried over sodium sulfate and then distilled. IR spectrum (CHCl ₃ ): 3080, 1800, 1660, 1630, _{1590, 990, 905 cm- '. NMR spectrum (CCJ 4} ): 633 ppm (1 H, d of d. J = 17 and 11 cps) 4.8-5.7 ppm (5 H. m), 3.91 ppm (2 H, s), 2 ^ ppm (4 H. m). 1.74 ppm (3 H, s).

b) Preparation of 4-methyl-8 vinyl-nonadien- (4,8) -al

To a cooled to -10 ⁰ C to -20 "C suspension of 770 mg of finely divided lithium in 20 ml of anhydrous ether was within 30 minutes under nitrogen, a solution of 8.23 g (58 millimoles) of methyl iodide in 15 ml of ether. The reaction mixture was during 1 hour at Cf C stirred whereupon a solution of 536 g ^{at -10 0 C within 20 minutes}

(55 millimoles) of diisopropylamine freshly distilled from sodium hydride was added. The reaction mixture was stirred for a ^{further 45 minutes at 0 °} C., evolution of gas being observed. After gas evolution had stopped, was inne.-t for 15 minutes at -10 ° C a solution of 7.5 g (75 mmol) ethylidene-tert-butyl imine in 5 ml of ether and after 20minutigem stirring at 1O ⁰ C within 15 Minutes at -20 ⁰ C a solution of 10.7 g (50 millimoles) of myrcenyl bromide in 5 ml of ether was added. The reaction mixture was stirred at room temperature overnight and then poured into a solution, cooled to 0 °, of 30 g of oxalic acid in 400 ml of water. After stirring for a further 20 minutes, the organic layer was separated off and the aqueous phase was extracted twice with ether. The ethereal extracts were washed with water, dried over sodium sulfate and distilled. 7.84 g of a liquid with a boiling point of 65-67 ° / 0.03 Torr were obtained, which was chromatographed on a column of 200 g of silica using 725 ml of hexane containing 3% ethyl acetate as the eluent. From the last fractions (together 450 ml), after evaporation of the solvent, 5.46 g (61%) of 90% pure 4-methyl-S vinyl-nonadiene- (4.8) -al with a b.p. = 60 "/ 0.02 Torr IR spectrum (CHCl _3):. 3080, 2720. 1790. 1720, 1590 16J0 990. 905 cm- 'UV spectrum (ethanol):... 2240 A (ε = 18600) NMR spectrum (CCI ₄ ): 9.73 ppm (1 H, J = 1.5 cps), 6.35 ppm (1 H, d of d,) = 17 and 10 cps) ίο 4.8-5.5 ppm (5 H, m ), 2.0-2.7 ppm (8 H. m), 1.61 ρριτ (3 H, s wide).
Analysis for Ci ₂ H] ₈ O:

Calculated: C 80.85, H 10.18%; found: C 80.84, H 10.44%.

c) / i-Sinensal

4-Methyl-8-vinyl-nonadien- (4,8) -al was in the in

Example 1 d) described manner treated. There· / 3-Sinensal was obtained in a comparable yield and had the same constants as that according to

Example 4 d) Product obtained.

Claims (6)

Patent claims: 1. Process for the preparation of /? - Sinensal of the formula: CHO 10 characterized in that one a) Myrcene on the non-conjugated double bond using a peracid in a buffered one The medium is epoxidized in such a way that the solution to be epoxidized and the epoxidizing agent are cooled while cooling at such a rate that the resulting Reaction temperature remains approximately constant; b) the myrcene epoxide obtained under basic conditions in the corresponding secondary Alcohol convicted; c) the latter with an unsubstituted vinyl ether in the presence of a mixture of a heavy metal salt and a stabilizer acting alkali metal salt condensed; d) the aldehyde obtained. 4-methyl-8-vinylnonadiene- (4.8) -al with an N-substituted propionalimine. whose substituent is a straight chain or branched aliphatic or alicyclic radical with 2 to 8 carbon atoms, in Condenses the presence of a metalation agent; e) the condensation product then in an at least partially aqueous acidic Medium hydrolyzed to j3-Sinensal. 2. The method according to claim 1, characterized in that that in stage a) using peracetic acid in the presence of sodium acetate in a chlorinated Epoxidized solvent. 3. The method according to claim 1, characterized in that: hnet, that step c) in the presence of a mixture of mercuric acetate and sodium acetate performs. 4. The method according to claim 1, characterized in that that the metalating agent in stage d) is the reaction product of an alkali metal with a Alkyl halide and a secondary amine are used. 5. The method according to claim 1, characterized in that that aqueous oxalic acid is used as the hydrolysis medium in stage e). 6. Modification of the method according to claim 1, characterized in that instead of the Steps a) to c) a myrcenyl halide of the formula